Metabolism of troglitazone in hepatocytes isolated from experimentally induced diabetic rats

被引:2
作者
Meechan, A. J.
Henderson, C.
Bates, C. D.
Grant, M. H.
Tettey, J. N. A.
机构
[1] Univ Strathclyde, Dept Pharmaceut Sci, Glasgow G4 0NR, Lanark, Scotland
[2] Univ Strathclyde, Bioengn Unit, Glasgow G4 0NR, Lanark, Scotland
关键词
D O I
10.1211/jpp.58.10.0009
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Troglitazone (TGZ), the prototype 2,4-thiazolidinedione antidiabetic agent, is associated with hepatotoxicity in patients with Type 2 diabetes. Although the mechanism of toxicity has not been established, alterations in the clearance of TGZ from in-vitro hepatocyte cultures through metabolic conjugation reactions are believed to modulate the toxicity of the compound. In this study, the metabolism of TGZ in freshly isolated hepatocytes from the fat-fed streptozotocin-treated rat model of Type 2 diabetes is described. Biochemical parameters such as cellular reduced glutathione content, content of cytochromes P450 and b(5), and the expression of glutathione-S-transferase alpha (subunits Y-a and Y-c2) were not affected by the induced diabetes. TGZ was metabolized primarily to a sulfonate, a quinone and a glucuronide in both control and experimentally diabetic animals. However, metabolism after induction of diabetes was characterized by a moderate increase in sulfation, a decrease in the elimination half-life of TGZ and the absence of the minor metabolites of TGZ, notably the glutathione adduct of the putative reactive intermediate (m/z= 747 (M + H)(+) m/z = 745 (M - H)(-)).
引用
收藏
页码:1359 / 1365
页数:7
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